Synthesis and biological evaluation of novel benzohydrazide derivatives of substituted quinazoline-2,4(1H,3H)-diones as Selective PARP-1 inhibitors with promising anti-proliferative activity
Tawfik S.S. Elhanafy E. Almehmadi S.J. Ewes W.A. Elkamhawy A. Elokely K.M. Elfeky S.M.
5 January 2026Elsevier B.V.
Journal of Molecular Structure
2026#1349
Poly(ADP-ribose) polymerase-1 (PARP-1) is a promising target for anticancer therapy. In this study, seventeen novel substituted quinazolin-2,4(1H,3H)‑dione derivatives were rationally designed, synthesized, and evaluated for their anti-proliferative activity against human cancer cell lines HCT-116, MCF-7, and PC3. Among these, compounds 7a and 7e exhibited the most potent cytotoxic effects, with EC₅₀ values ranging from 2.95 to 10.03 μM. They exhibited selective cytotoxicity towards tumor cell lines compared to normal cell lines, with EC50 values of 87.92±4.1 μM and 51.84±2.9 μM, respectively, against WI38 cell lines. Mechanistic studies, including enzymatic assays, showed both compounds to be selective inhibitors of PARP-1 over PARP-2; where 7a and 7e showed PARP-1 inhibitory EC₅₀ values of 0.068±0.0027 μM and 0.024±0.0009 μM, respectively, compared to Olaparib (0.040±0.002 μM). For PARP-2, 7a and 7e exhibited EC₅₀ = 0.357±0.014 μM and 0.119±0.005 μM, respectively, confirming their selectivity. In DNA-trapping experiments, 7a and 7e demonstrated EC₅₀ = 2.720 μM and 0.890 μM, respectively. According to molecular docking studies, both compounds bind to PARP-2 less favorably and occupy the PARP-1 active site similarly to Olaparib, forming important π-π stacking and hydrogen-bonding interactions. In contrast to the unstable binding seen in the PARP-2 complex, molecular dynamics simulations conducted over a 50 ns period further confirmed that 7a binds selectively to PARP-1, exhibiting stable interactions and few conformational fluctuations. Favorable pharmacokinetic profiles, such as high oral bioavailability, drug-likeness, and the lack of anticipated hepatotoxicity, CNS liability, or carcinogenicity, were predicted by in silico ADMET analysis for 7a and 7e. When taken as a whole, these results show that 7a and 7e are promising lead compounds for the development of novel selective PARP-1 inhibitors for cancer treatment.
3H) diones , ADMET , Anticancer activity , Molecular docking , Molecular Dynamic simulation , PARP-1 , Quinazolin-2,4(1H , Ultrasound
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Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 355516, Egypt
Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Mecca, 24451, Saudi Arabia
Department of Chemistry, School of Sciences and Humanities, Nazarbayev University, Astana, 010000, Kazakhstan
Division of Pharmaceutical Sciences, School of Pharmacy, College of Health Sciences, University of Wyoming, Laramie, 82071, WY, United States
Department of Pharmaceutical Organic Chemistry
Biomedical Sciences Program
Department of Chemistry
Department of Chemistry
Division of Pharmaceutical Sciences
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Книга Публикация научной статьи Волощук 2026 Book Publication of a scientific article 2026